Human diseases vectored by mosquitoes are a significant public health concern, and novel and innovative methods to prevent the spread of vector borne diseases are in high demand. Because these pathogens must infect a mosquito in order to be transmitted to humans, it is possible to interrupt the transmission cycle by preventing infections in mosquitoes. Recent research has demonstrated that the microbes in the mosquito gut can influence the infectivity of pathogens causing diseases such as malaria and dengue. Moreover, certain species of bacteria have been shown to have direct anti-pathogen activity on these and other vector borne diseases. Previous work has revealed that the mosquito gut microbiota can be highly variable. The present proposal aims to determine key genetic factors and predict mechanisms that underlie variability in the size and composition of the gut microbiota of Aedes aegypti mosquitoes. This will be accomplished by comparing the gene expression patterns across strains of Aedes that vary in gut microbiota size and composition. Genes of interest will be identified in an unbiased fashion, through the use of whole-genome gene expression microarray analysis, and confirmed for their role in shaping the gut microbiota using gene-specific gene expression studies and RNAi knockdown functional analyses. Candidate genes will also be tested for their implications in influencing the gut microbiota in fied mosquitoes collected in dengue endemic areas of Puerto Rico. This work will provide important insight into the molecular factors and mechanisms that shape the mosquito gut microbiota and contribute to its variability, which has been shown to influence vector competence. This information will advance our knowledge of mosquito gut immunity and will have important implications for the development of novel disease control strategies based on manipulation of the mosquito gut microbiota.